A new paper published in the journal Brain, Behavior and Immunity in the past week – as a result of a collaboration between research groups in Norway and Germany – is an important contribution to our understanding as to which people may or may not respond to rituximab. The abstract appears beneath Professor Edwards’ comments.
I need to look at the paper in detail but I think these are important findings.
The only caveat to flag up is that muscarinic ACh receptor antibodies have a reputation for being a bit of a pain in terms of reproducibility but I would not worry too much about that.
It is good to see dynamic results – i.e. changing with treatment.
It is also great to see the Norwegian/German collaboration bearing fruit.
There is a lot more work to do but this is very promising.
It is hard to answer the question about implications specifically.
However, if it proves possible to select cases for rituximab based on data like this then that makes a huge difference to getting a therapeutic programme of the ground.
One of the most important brakes on the programme is the worry that treatments like rituximab would have to be used hit and miss in a condition that is hard to pin down diagnostically and that may include people for whom this is the wrong approach.
Take away that worry and treating ME by B cell targeting begins to look much more similar to lots of other diseases.
The discussion at Phoenix Rising can be read here:
From Brain, Behavior and Immunity, 21 September 2015.
Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome
Loebel M(1), Grabowski P(2), Heidecke H(3), Bauer S(2), Hanitsch LG(2), Wittke K(2), Meisel C(4), Reinke P(5), Volk HD(6), Fluge Ø(7), Mella O(8), Scheibenbogen C(6).
1) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. Electronic address: firstname.lastname@example.org.
2) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
3) CellTrend GmbH, Luckenwalde, Brandenburg, Germany.
4) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
5) Department of Nephrology, Charité University Medicine Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
6) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
7) Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
8) Department of Oncology and Medical Physics, Haukeland University Hospital, and Department of Clinical Science, University of Bergen, Bergen, Norway.
• β adrenergic and muscarinic acetylcholine receptor autoantibodies are elevated in a subset of patients with Chronic Fatigue Syndrome (CFS).
• Elevated autoantibodies in CFS correlate with elevated IgG1-3 subclass levels, thyreoperoxidase and ANA antibodies and T cell activation.
• In CFS patients responding to rituximab treatment, elevated antibody levels detected pre-treatment normalized in the majority of clinical responders post-treatment.
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors.
Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108).
Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls.
A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies.
In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.
We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.